Global Regulatory DNA Potentiation by SMARCA4 Propagates to Selective Gene Expression Programs via Domain-Level Remodeling
John E. Lazar,
Sandra Stehling-Sun,
Vivek Nandakumar,
Hao Wang,
Daniel R. Chee,
Nicholas P. Howard,
Reyes Acosta,
Douglass Dunn,
Morgan Diegel,
Fidencio Neri,
Andres Castillo,
Sean Ibarrientos,
Kristen Lee,
Ninnia Lescano,
Ben Van Biber,
Jemma Nelson,
Jessica Halow,
Richard Sandstrom,
Daniel Bates,
Fyodor D. Urnov,
Alister P.W. Funnell,
John A. Stamatoyannopoulos
Affiliations
John E. Lazar
Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; Altius Institute for Biomedical Sciences, Seattle, WA 98121, USA
Sandra Stehling-Sun
Altius Institute for Biomedical Sciences, Seattle, WA 98121, USA
Vivek Nandakumar
Altius Institute for Biomedical Sciences, Seattle, WA 98121, USA
Hao Wang
Altius Institute for Biomedical Sciences, Seattle, WA 98121, USA
Daniel R. Chee
Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; Altius Institute for Biomedical Sciences, Seattle, WA 98121, USA
Nicholas P. Howard
Altius Institute for Biomedical Sciences, Seattle, WA 98121, USA
Reyes Acosta
Altius Institute for Biomedical Sciences, Seattle, WA 98121, USA
Douglass Dunn
Altius Institute for Biomedical Sciences, Seattle, WA 98121, USA
Morgan Diegel
Altius Institute for Biomedical Sciences, Seattle, WA 98121, USA
Fidencio Neri
Altius Institute for Biomedical Sciences, Seattle, WA 98121, USA
Andres Castillo
Altius Institute for Biomedical Sciences, Seattle, WA 98121, USA
Sean Ibarrientos
Altius Institute for Biomedical Sciences, Seattle, WA 98121, USA
Kristen Lee
Altius Institute for Biomedical Sciences, Seattle, WA 98121, USA
Ninnia Lescano
Altius Institute for Biomedical Sciences, Seattle, WA 98121, USA
Ben Van Biber
Altius Institute for Biomedical Sciences, Seattle, WA 98121, USA
Jemma Nelson
Altius Institute for Biomedical Sciences, Seattle, WA 98121, USA
Jessica Halow
Altius Institute for Biomedical Sciences, Seattle, WA 98121, USA
Richard Sandstrom
Altius Institute for Biomedical Sciences, Seattle, WA 98121, USA
Daniel Bates
Altius Institute for Biomedical Sciences, Seattle, WA 98121, USA
Fyodor D. Urnov
Altius Institute for Biomedical Sciences, Seattle, WA 98121, USA
Alister P.W. Funnell
Altius Institute for Biomedical Sciences, Seattle, WA 98121, USA; Corresponding author
John A. Stamatoyannopoulos
Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; Altius Institute for Biomedical Sciences, Seattle, WA 98121, USA; Corresponding author
Summary: The human genome encodes millions of regulatory elements, of which only a small fraction are active within a given cell type. Little is known about the global impact of chromatin remodelers on regulatory DNA landscapes and how this translates to gene expression. We use precision genome engineering to reawaken homozygously inactivated SMARCA4, a central ATPase of the human SWI/SNF chromatin remodeling complex, in lung adenocarcinoma cells. Here, we combine DNase I hypersensitivity, histone modification, and transcriptional profiling to show that SMARCA4 dramatically increases both the number and magnitude of accessible chromatin sites genome-wide, chiefly by unmasking sites of low regulatory factor occupancy. By contrast, transcriptional changes are concentrated within well-demarcated remodeling domains wherein expression of specific genes is gated by both distal element activation and promoter chromatin configuration. Our results provide a perspective on how global chromatin remodeling activity is translated to gene expression via regulatory DNA.